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R T Oliver

Publications and source records attributed to R T Oliver.

At least 91 records · Page 5Linked to original sources
PubMed1995

Candidate regions for a testicular cancer susceptibility gene.

Epidemiological data suggest the presence of a susceptibility gene for testicular cancer in some families. Families with multiple cases of testicular cancer are rare and almost all those reported have only two affected members. We have performed a sib-pair analysis on 35 families in which there are either two or three affected brothers. These families have been typed for 220 autosomal microsatellite markers spaced 10-20 cM throughout the genome. Six regions which gave a LOD score of more than 1.0 on formal linkage analysis or a P value of 0.05 or less using a non-parametric approach are considered as candidate regions for a susceptibility gene. Of particular interest is one region on chromosome 4. Two neighbouring probes in this region both scored positively with LOD score of 2.60 on multipoint analysis. An International Testis Cancer Linkage Consortium has been formed to pool resources and will investigate these findings further with the world-wide collection of families.

Genetic Linkage↗
PubMed1995

Secondary tumours following etoposide containing therapy for germ cell cancer.

BACKGROUND: Reports have implied etoposide as the cause of secondary leukaemia in patients treated for germ cell cancer. PATIENTS AND METHODS: Between 1979 and 1992, 679 male patients with germ cell cancer received etoposide containing chemotherapy. RESULTS: Six of 679 patients developed acute myeloid leukaemia (relative risk 150; CI: 55-326). None of these patients had a primary mediastinal germ cell tumour and only 1 patient received previous radiotherapy. The median interval between the onset of cytotoxic treatment and the development of leukaemia was 27 months. The FAB M4 morphology was seen in 4 of 6 cases. CONCLUSION: The benefit of etoposide containing protocols outweigh the risk of leukaemia in patients with intermediate or high risk disease, however in patients with good risk disease non-etoposide containing protocols should be explored.

Acute Disease↗
PubMed1995

Germ cell cancer of the testes.

New insights into the etiology and specifically the role of atrophy in generating increased gonadotropin drive have come from a case-control study of 794 patients. This study demonstrated possible evidence for trauma and infection-related atrophy, although of most interest from the point of view of the gonadotropin drive hypothesis is the observation that, as with breast cancer, exercise may reduce the risk and early onset of puberty may increase the risk. The value of self-examination education as a way of reducing delay in diagnosis was debated from the viewpoint of general practice. This provided a timely reminder that, in a rare tumor with a more than 95% cure rate, such education might generate more anxiety about the disease than it would early diagnoses. The total absence of carcinoma in situ at the time of orchidectomy in a series of cryptorchidic patients who subsequently developed testis cancer after orchidopexy provides a good reason for not performing a biopsy. The late nongerm cancers at 15 to 20 years after radiation therapy have provoked reexamination of priorities for stage I seminoma. New data from two centers that have used a single course of carboplatin as adjuvant therapy with no relapses in 104 patients are of considerable interest in providing an alternative to radiation therapy.

Germinoma↗
PubMed1995

Castration-induced lymphocytosis in prostate cancer: possible evidence for gonad/thymus endocrine interaction in man.

Prompted by evidence from animal studies that castration produces lymphocytosis associated with thymic hyperplasia, this paper has reviewed serial lymphocyte levels in patients with prostate cancer undergoing hormone treatment. On day 7, 5 of 12 patients (58%) showed diminished circulating lymphocyte levels (compared to day 0) reflecting the surge of testosterone after treatment with LHRH analogues, while on day 28 a reversal had occurred and 13 of 17 (77%) had increased lymphocytes (compared to day 0). Possible relevance of these observations to defining a subgroup of patients with hormone-sensitive cancer who might benefit from immunotherapy is discussed.

Castration↗
PubMed1995

Intermittent endocrine therapy and its potential for chemoprevention of prostate cancer.

This chapter has reviewed the limitations of the use of chemotherapy in patients with hormone resistant prostate cancer. Although demonstrating that there is a small number of patients with very chemosensitive tumours, the age profile and intolerance to chemotherapy make it highly unlikely that this modality of treatment will be used more routinely despite the increasing evidence that the slow decline of prostate specific antigen with endocrine treatment can be used early to select patients who might respond to chemotherapy. Equally certain is that it will not be of use for chemoprevention of the early stages of this disease. Although some data suggest that tumours that respond rapidly and completely to endocrine therapy may benefit from the use of non-specific immunotherapy, there is no evidence that any form of vaccination therapy would be of value in preventing the disease in the main because all attempts to find evidence of a virus, particularly a human papillomavirus subtype, involved in its aetiology have proved negative. The discovery that standard endocrine therapy induces thymic regeneration and peripheral blood lymphocytosis, taken together with the demonstration that surgical trauma induced by a needle biopsy could accelerate tumour dissemination because of tumour activation by trauma induced release of tissue repair cytokines, has led to the proposal that short term endocrine treatment should be given to all prostate specific antigen positive patients prior to needle biopsy. New information on the slow kinetics of prostate cancer growth, with cancers detected by screening being found up to 20 years before clinical presentation and more than 80% of early tumours failing to double the prostate specific antigen level within 2 years, has led to proposals for a new strategy for endocrine chemoprevention of prostate cancer. This has in part been encouraged by greater confidence in the use of intermittent hormone therapy to treat patients with metastatic disease. These observations have led to the suggestion that it might be possible to prevent deaths by treating early cases detected from prostate specific antigen screening with short term (1-3 months) endocrine treatment every 5 to 10 years.

Androgen Antagonists↗
PubMed1994

On the development of the Medical Research Council trial of alpha-interferon in metastatic renal carcinoma. Urological Working Party Renal Carcinoma Subgroup.

This paper describes the steps taken by the British Medical Research Council (MRC) in developing the MRC RE01 trial, a randomized clinical trial for patients with metastatic renal cancer; we discuss the reasons for adopting a triangular sequential design and the impact that this has upon the monitoring of the trial. It had been suggested to the MRC that a trial of biological agents for metastatic renal carcinoma should be initiated. The Cancer Therapy Committee (CTC) of the MRC, through its associated site specific working parties, is responsible for designing and co-ordinating randomized trials of alternative treatments in cancer in solid tumours. Since no MRC working party for renal carcinoma existed at that time, development began by the formation of an ad hoc group set up under the auspices of the CTC. They assessed, by means of a postal questionnaire, U.K. interest in the trials of, and modalities utilized for, treatment of renal cancer. The responses focused attention on the important questions to ask and indicated the level of potential collaboration. These responses and related clinical and statistical issues suggested a protocol to compare medroxy-progesterone acetate (MPA) against alpha-interferon (alpha-IFN). In view of the special problems of comparing an expensive and potentially toxic therapy with an inexpensive and non-toxic standard, a sequential design was used rather than a fixed sample size design. Statistical issues raised and solutions provided are described. The method of establishing the trial data monitoring committee and a brief review of mortality from renal carcinoma in England and Wales are also included. The trial opened to patient recruitment on 1 January 1992. The formal statements regarding statistical issues that appear in the formal trial protocol (RE01) are set out in the Appendix.

Aged↗
PubMed1994

Pilot studies of 2 and 1 course carboplatin as adjuvant for stage I seminoma: should it be tested in a randomized trial against radiotherapy?

PURPOSE: Underpinned by increased confidence in cure of metastatic seminoma by chemotherapy during the past 12 years, three management strategies for Stage I seminoma have been evaluated by six collaborating centers within the Anglian Germ Cell Tumor Group. This paper evaluates the efficacy of surveillance, prophylactic radiotherapy and adjuvant chemotherapy, and discusses these differing management approaches. METHODS AND MATERIALS: Patients were recruited into the study between 1982 and 1992. There was no randomization between treatment groups. Seventy-nine patients received prophylactic radiotherapy (median follow-up = 51 months), 67 patients had surveillance alone (median follow-up = 61 months) and 78 patients were treated with adjuvant single agent platinum (median follow-up = 44 months). Fifty-three of these patients received two courses of platinum (median follow-up = 51 months) and 25 patients received one course (median follow-up = 29 months, range 22-72 months). RESULTS: There were 18 (27%) recurrences on surveillance, five (6%) after radiotherapy, one (1%) after two courses of adjuvant single agent platinum and none after one course of carboplatin. There was one death from testis cancer after radiotherapy and none after adjuvant chemotherapy treatments. Two patients died with drug resistant disease after relapse on surveillance. There was one death from a myocardial infarction after prophylactic radiotherapy and one death from suicide in the surveillance group. A retrospective quality of life questionnaire reviewing the incidence of early and late toxicity revealed no major differences though they suggest that those treated with one course adjuvant carboplatin had somewhat less sickness and an earlier return to work. CONCLUSION: Single agent carboplatin appears well tolerated and is an effective adjuvant treatment for Stage I seminoma. A multicenter randomized trial of the different treatment modalities is required to further evaluate its use.

Adult↗
PubMed1994

Clinical and immunological effect of intravesical interleukin-2 on superficial bladder cancer.

Using immunocytochemical techniques the pattern of T cell markers and MHC antigens on peripheral blood mononuclear cells, and tumour biopsies of patients with superficial bladder cancer before and after intravesical human recombinant interleukin-2 (rhuIL-2) therapy (three cases at 1 MIU, four cases at 18 MIU and two cases at 54 MIU), was investigated. There was a slight but significant increase in the total number of circulating leucocytes, harvested from blood using density gradient technique, after intravesical rhuIL-2 treatment. Thus the mean +/- SD of seven cases before and after (more than 30 days of) IL-2 were 1.24 +/- 0.32 x 10(9)/l and 1.50 +/- 0.46 x 10(9)/l respectively (t-test, P = 0.032). However, this was substantially less than in samples collected after subcutaneously (six cases) and intravenously (seven cases) administering rhuIL-2, the results of which were 1.09 +/- 0.46 x 10(9)/l versus 2.22 +/- 0.68 x 10(9)/l (P = 0.016) and 0.84 x 10(9)/l versus 2.3 x 10(9)/l (P = 0.004) respectively. There was no demonstrable alteration in the percentage of cells positive for CD3, CD4, CD8, CD25 or CD56 in peripheral blood or urine populations in six patients treated with intravesical IL-2, or the pattern of MHC class I or II expression on tumour biopsies before and after treatment. Though this could have been a reflection of the fact that most of the cases had normal class I expression, there was one tumour with complete loss and one tumour with very low expression among the three cases showing stroma positivity for HLA-A3 antigens. Neither of these was altered by IL-2 treatment, nor was class II antigen expression, which was positive in five of nine cases before treatment. Given the lack of the expected major immunological changes and the poor clinical responses (one of nine complete responses lasted 3 months), it is concluded that the schedule has not produced an adequate dose intensity to induce lymphocyte activation and alternative schedules based on those developed from systemic treatment need exploration.

Administration, Intravesical↗
PubMed1994

Testicular cancer.

The human genome project has revolutionized technology for the study of DNA. Several of this year's papers have applied these techniques to the study of testicular cancer, especially the use of double-fluorescence in situ hybridization to identify the germ cell tumor marker isochrome 12p in tissue sections, and loss-of-heterozygosity studies to demonstrate a candidate suppressor gene on the long arm of the same chromosome that may be a ligand for the c-kit protooncogene. The report of a solitary case of a patient with a tumor (in a solitary testis) who was treated by partial orchiectomy and then fathered two children emphasizes the need for more information on fertility of patients with carcinoma in situ before the highly effective low-dose radiation to the testis can be accepted. The confirmation of the occurrence of acute myeloid leukemia as a late effect of etoposide and stomach cancer as a late effect of radiotherapy for stage I seminoma has drawn attention to the need to reduce treatment in good-risk patients. Results of trials substituting cisplatin with carboplatin and a trial eliminating bleomycin are particularly disappointing, and the 10% lower cures with the experimental regimen in these studies is an object lesson of the risks involved in such studies. Two other issues that continue to be debated include the increasing recognition of the value of lactate dehydrogenase-1 for identifying poor-risk patients, and the benefits of referral to a unit specializing in testicular cancer. There is an increasing trend to use high-dose chemotherapy for previously untreated patients who have poor risk factors. who have poor risk factors.

Carcinoma in Situ↗
PubMed1994

The frequency of major histocompatibility complex antigen abnormalities in urological tumours and their correction by gene transfection or cytokine stimulation.

There is increasing evidence that loss of major histocompatibility complex (MHC) antigens from tumors may be a factor in escape from immune surveillance. In an attempt to quantify this phenomenon in bladder tumors, frozen sections were stained immunochemically and cell lines were tested in a radiobinding assay before and after treatment with interferon gamma (IFN gamma) and after attempts to correct the defect by normal human leukocyte antigen (HLA) gene transfection. Study of 68 tumor sections with W6/32 antibody against monomorphic class I demonstrated that 42% had reduced or absent staining compared with the intensity of stromal staining. Ten percent of cases had complete absence with W6/32, all of which were also negative for beta 2-microglobulin (beta 2-m) expression. Use of polymorphic antibodies for A2, A3, Bw4, and Bw6 increased this frequency of defects to 73%. Study of 21 tumor cell lines with W6/32 demonstrated negative staining in five (23%) that could not be induced by IFN gamma and reduced staining in three (14%) that could be increased by IFN gamma, the remainder showing normal levels unaffected by IFN gamma. An additional six (28%) failed to express class II in response to IFN gamma, leading to an overall incidence of abnormality of 65%. In no case did cotransfection of one cell line with a defect in one case transfection of beta 2-m gene into a class I negative line of fully assembled MHC class I antigens. It is concluded that the majority of tumor cells demonstrate some form of MHC class I and II defects.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigens, Neoplasm↗
PubMed1994

Partial orchidectomy for second testicular tumour.

This report describes a patient who underwent a partial orchidectomy for testicular cancer, having already had a radical orchidectomy of the contra lateral side. He subsequently fathered two children. This policy may have a role in the management of men with an early germ cell tumour in a solitary testis who have not completed their family.

Adult↗
PubMed1993

Accurate and rapid assessment of MHC antigen upregulation following cytokine stimulation.

Three human tumour cell lines, A431 (cervical), Scaber (bladder) and Fen (bladder), were studied using immunohistochemical staining (IC), radiobinding (RB), immunoprecipitation (IP), enzyme-linked immunosorbent assay (ELISA) and dot-blot (DB) techniques in order to assess major histocompatibility antigen (MHC) induction in response to interferon-gamma (IFN-gamma). Induction of class II antigens by IFN-gamma was observed on all three cell lines using all techniques. Monoclonal antibody (Mab) staining showed that both Scaber and A431 lines were positive for intact class I (Mab W6/32), class I free heavy chain (Mab HC10) and beta 2 microglobulin (beta 2-m) (Mab BBM.1), while Fen cells were positive only with HC10. The IP technique demonstrated the presence of a 45 kDa band on precipitation of the Fen lysate with HC10 Mab, whereas no such band was observed when W6/32 was used. The DB technique confirmed the negative reaction with W6/32 and BBM.1 Mabs, while HC10 showed positive staining which was upregulated by IFN-gamma. Transfection of the Fen cells with the beta 2-m gene resulted in the surface expression of fully assembled class I molecules. The DB technique showed upregulation of class I antigens following IFN-gamma stimulation, while RB detected no significant increase in cell surface expression (t test; p = 0.104). The binding values for transfected Fen cells before and after IFN-gamma stimulation were 2000 +/- 48 and 2161 +/- 156 cpm respectively. These results demonstrate that the DB technique facilitates an accurate assessment of cytokine induced antigens, corrected against a background of total cellular protein synthesis. The ease of execution, simplicity, non-radioactive nature and economy make it the method of choice for routine screening prior to the selection of suitable patients for cytokine therapy.

Antigens, Neoplasm↗
PubMed1993

A new approach for measurement of cytotoxicity using colorimetric assay.

Using in vitro established tumour cell lines attempts were made to assess the suitability of tetrazolium salt reduction (MTT) assay to replace the conventional radioactive base techniques for measuring cell proliferation and cell killing. The optimum conditions for MTT loading time, concentration of MTT and the time for colour development were found to be 4 h, 5 mg/ml and 30 min respectively, conditions which were used for subsequent experiments. Analysis of the correlation between increasing cell numbers and optical densities (OD) showed a direct relationship with correlation of coefficient values of r > 0.98 and 10,000 cells/well was found to provide an accurate ODs for a wide variety of cell types. The accuracy of replicate readings of the assay was investigated by setting a wide range of cell numbers and the variation among seven replicates was calculated and found to be less that 6% of the mean values. The reproducibility of the assay for two cell lines was tested using the lines on four different occasions. The ODs for Jar and Fen cell lines were 0.80 +/- 0.01, 0.82 +/- 0.02, 0.90 +/- 0.02, 0.79 +/- 0.05 and 0.56 +/- 0.01, 0.58 +/- 0.03, 0.60 +/- 0.02 and 0.61 +/- 0.02 respectively giving maximum variation of less than 11% of mean on repeated testings. Comparison between the results of MTT with 3H-Tdr or 51Cr release assays showed a high degree of correlation over a wide range of cell numbers and cell types. The r values between the results of MTT with 3H-Tdr (for cell number ranging from 1.8 to 60 x 10(3)/well) or 51Cr release assays (for E/T ratios of between 5:1 and 40:1) were 0.89 (p = 0.001) and 0.96 (p < 0.03) respectively. These results demonstrate that it is possible to use the MTT assay interchangeably with radioactive base techniques to measure cell proliferation and cytotoxicity. The ease of its execution, safety and its suitability for analysing as few as 3000 cells makes this method a serious contender for replacing the conventional radioactive techniques.

Cell Division↗
PubMed1993

Generation of cytotoxic T lymphocytes from peripheral blood of leukaemic patients.

Peripheral blood mononuclear cells from 13 patients with acute leukaemia were used to establish long-term interleukin-2-dependent cytotoxic T lymphocytes. Cells were grown in RPMI medium containing interleukin-2 (IL-2, 100 U/ml) and 2.5% conditioned medium prepared by activating normal lymphocytes with phytohaemagglutinin. Proliferation of IL-2-dependent CD3-positive lymphocytes was seen in 1 of 2 acute lymphocytic leukaemia cases (ALL), 1 of 4 acute myelogenous leukaemia cases (AML) (M1) and 8 of 8 more differentiated AML. In 2 cases with detectable leukaemic cell markers (1 ALL and 1 AML) passageable cells were developed, that expressed normal T cell phenotypes (namely CD3, CD4 and CD8) at the expense of leukaemic cells. In 1 of 2 cases, long-term IL-2-cultured cells showed specific cytotoxic activity against autologous leukemic cells. The percentage killing against autologous and two allogeneic target cell lines at a 50/1 effector/target (E/T) ratio was 42%, 9% and 19% respectively. Similarly the cytotoxic activity of IL-2 activated from 4 different individuals against conventional tumour targets K562 and Daudi at a ratio of 50/1 was 29%-68% (median = 55%) and 34%-78% (median = 61%) respectively. It was also found that this killing potential of the activated cells was maintained for as long as culture was continued (median 23 days, range 17-75 days). The mechanism(s) of T cell proliferation at the expense of leukaemic blast cells in the case of a minority of leukaemic patients and the possible clinical therapeutic potential of these cells following in vitro IL-2 activation deserve further investigation.

Antigens, CD↗